EP2985294A1 - Molécule d'anticorps de recombinaison et son utilisation pour l'activation des lymphocytes T restreints de cellule cible - Google Patents

Molécule d'anticorps de recombinaison et son utilisation pour l'activation des lymphocytes T restreints de cellule cible Download PDF

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Publication number
EP2985294A1
EP2985294A1 EP14181060.6A EP14181060A EP2985294A1 EP 2985294 A1 EP2985294 A1 EP 2985294A1 EP 14181060 A EP14181060 A EP 14181060A EP 2985294 A1 EP2985294 A1 EP 2985294A1
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European Patent Office
Prior art keywords
domain
antibody molecule
binding site
antigen
antibody
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EP14181060.6A
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German (de)
English (en)
Inventor
Gundram Jung
Helmut R. Salih
Gernot Stuhler
Ludger Grosse-Hovest
Berit Lochmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
German Cancer Research Center
Eberhard Karls Universität Tübingen
University of Würzburg
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German Cancer Research Center
Eberhard Karls Universität Tübingen
University of Würzburg
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Application filed by German Cancer Research Center, Eberhard Karls Universität Tübingen, University of Würzburg filed Critical German Cancer Research Center
Priority to EP14181060.6A priority Critical patent/EP2985294A1/fr
Priority to EP15757154.8A priority patent/EP3180361B1/fr
Priority to DK15757154.8T priority patent/DK3180361T3/da
Priority to US15/503,703 priority patent/US20180208657A1/en
Priority to PCT/EP2015/068482 priority patent/WO2016023909A1/fr
Priority to ES15757154T priority patent/ES3008567T3/es
Publication of EP2985294A1 publication Critical patent/EP2985294A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2863—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3053—Skin, nerves, brain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/524—CH2 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/53—Hinge
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/55—Fab or Fab'
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/64—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising a combination of variable region and constant region components
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/71—Decreased effector function due to an Fc-modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • bispecific antibodies directed to a tumor associated antigen (TAA) and the T cell receptor (TCR)/CD3-complex are capable of activating T cells and mediate the lysis of TAA expressing tumor cells by the activated T cells [1-3].
  • TAA tumor associated antigen
  • TCR T cell receptor
  • CD3-antibodies, bound to Fc receptors (FcRs) via their Fc-part, are exceedingly efficient in inducing T cell activation and cytokine release, it is of importance to construct Fc-depleted or -attenuated bispecific CD3-antibodies in order to prevent FcR binding and to allow for a target cell restricted- rather than FcR-mediated activation of T cells [4,5].
  • the entire heavy chain domains of an antibody molecule according to the invention have at least about 60 %, at least about 70 %, at least about 75 %, at least about 80 %, at least about 85 %, at least about 90 %, at least about 92 %, at least about 95 %, at least about 97 %, at least about 98 % or at least about 99 % sequence identity with the corresponding regions of an immunoglobulin mu heavy chain, of an immunoglobulin gamma heavy chain (such as gamma 1, gamma 2, gamma 3 or gamma 4 heavy chains), of an immunoglobulin alpha heavy chain (such as alpha 1 or alpha 2 heavy chains), of an immunoglobulin delta heavy chain or of an immunoglobulin epsilon heavy chain.
  • an immunoglobulin mu heavy chain such as gamma 1, gamma 2, gamma 3 or gamma 4 heavy chains
  • an immunoglobulin alpha heavy chain such as alpha 1 or alpha 2
  • a bispecific heterodimeric antibody molecule can comprise a hetero-dimer of the antibody molecule such as a recombinant antibody molecule of the present invention (Fabv molecule), wherein the first monomer of the hetero-dimer consists of a Fab fragment comprising a first binding site for a first antigen, a variable domain of the heavy chain of a second binding site for a second antigen and an immunoglobulin CH2 domain, wherein the Fab fragment and the variable domain of the heavy chain are linked via the CH2 domain, and wherein the second monomer of the hetero-dimer consists of a Fab fragment comprising a first binding site for the first antigen, a variable domain of the light chain of the second binding site for the second antigen and an immunoglobulin CH2 domain, wherein the Fab fragment and the variable domain of the light chain are linked via the CH2 domain, wherein the variable domain of the light chain of the second binding site of the first monomer and the variable domain of the heavy chain of the second binding site of Fab
  • chimeric antibodies which generally have a non-human (e.g. rodent such as mouse) variable domain fused to a human constant region. Because the antigen-binding site of an antibody is defined by residues within the variable domains the chimeric antibody retains its binding affinity for the antigen but acquires the effector functions of the human constant region and are therefore able to perform effector functions such as described supra.
  • Chimeric antibodies are typically produced using recombinant DNA methods.
  • “Complement dependent cytotoxicity” or “CDC” refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (Clq) to antibodies (of the appropriate subclass) which are bound to their cognate antigen.
  • a CDC assay e.g., as described in Gazzano-Santoro et al., J. Immunol. Methods 202: 163 (1997 ) may be performed.
  • codons for other amino acids such as selenocystein or pyrrolysine can also be incorporated into a nucleic acid of a antibody molecule. It is also possible, as described by Wang, L., et al. (2001) Science 292, 498-500 , or Wang, L., and Schultz, P.G. (2002) Chem. Comm. 1, 1-11 , to use "artificial" codons such as UAG which are usually recognized as stop codons in order to insert other unusual amino acids, for example o-methyl-L-tyrosine or p-aminophenylalanine.
  • Each of the cysteine residues at positions 226 and 229 (numbering of sequence positions according to the EU-index) (in the hinge region) of the native sequence at sequence positions 226 to 237 CPPCPAPELLGG (SEQ ID NO: 99, numbering according to the EU-index) was replaced by a serine residue.
  • the amino acid residues ELLG at positions 233-236 in the CH2 domain were exchanged (the exchanged amino acids were shaded in grey; also compare Fig. 2I ) as follows: Glu233 was substituted by Pro, Leu234 was substutited by Val, Leu235 was substituted by Ala, and Gly236 was deleted.
  • the replacements at positions 226 and 229 lead to a loss of cysteins, thereby preventing the formation of disulfide bridges.
  • the amino acid replacements at positions 233-236, 265, 297, 327, 330 lead to an attenuation of Fc function.
  • the original vector for the heavy chain contains the human ⁇ 1 isotype Ig heavy chain ( Fig. 7A ). Restriction sites were introduced at the required positions in introns in order to exchange the Aatll-Clal fragment with the VDJ fragment of the heavy chain of monoclonal antibodies 4G8 (anti-Flt3), BV10 (anti-FLT3), 4G7 (anti-CD19), C225 (anti-EGFR) and 9.2.27 (anti-CSPG4).
  • the AatII-ClaI fragment can also be exchanged with the VDJ fragment of the heavy chain of any other monoclonal antibody.
  • the region relevant for cloning the VDJ fragment is shown enlarged in Figure 7B .
  • Recombinant antibody molecules were purified from supernatants of cultures of stably transfected cells via affinity chromatography using KappaSelect for the Fabv- ko format (chromatography media were obtained from GE Healthcare, Kunststoff, Germany, KappaSelect has as affinity ligand a recombinant protein (Mr 13 000), produced in S. cerevisiae, with affinity for the constant domain of the immunoglobulin kappa light chain).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
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  • Biomedical Technology (AREA)
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  • Peptides Or Proteins (AREA)
EP14181060.6A 2014-08-14 2014-08-14 Molécule d'anticorps de recombinaison et son utilisation pour l'activation des lymphocytes T restreints de cellule cible Withdrawn EP2985294A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP14181060.6A EP2985294A1 (fr) 2014-08-14 2014-08-14 Molécule d'anticorps de recombinaison et son utilisation pour l'activation des lymphocytes T restreints de cellule cible
EP15757154.8A EP3180361B1 (fr) 2014-08-14 2015-08-11 Molécule d'anticorps de recombinaison et son utilisation pour l'activation des lymphocytes t restreints de cellule cible
DK15757154.8T DK3180361T3 (da) 2014-08-14 2015-08-11 Rekombinant antistofmolekyle og dets anvendelse til målcellebegrænset t celleaktivering
US15/503,703 US20180208657A1 (en) 2014-08-14 2015-08-11 Recombinant antibody molecule and its use for target cell restricted t cell activation
PCT/EP2015/068482 WO2016023909A1 (fr) 2014-08-14 2015-08-11 Molécule d'anticorps recombinant et son utilisation pour l'activation de lymphocytes t restreints à une cellule cible
ES15757154T ES3008567T3 (en) 2014-08-14 2015-08-11 Recombinant antibody molecule and its use for target cell restricted t cell activation

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EP14181060.6A EP2985294A1 (fr) 2014-08-14 2014-08-14 Molécule d'anticorps de recombinaison et son utilisation pour l'activation des lymphocytes T restreints de cellule cible

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WO (1) WO2016023909A1 (fr)

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JP2020529422A (ja) * 2017-08-01 2020-10-08 ユリウス−マクシミリアン−ウニヴェルシテート・ヴュルツブルク 急性骨髄性白血病を治療するためのｆｌｔ３ ｃａｒ−ｔ細胞及びｆｌｔ３阻害剤の使用
US20230052646A1 (en) * 2019-12-24 2023-02-16 Jjp Biologics Sp. Z O.O. Anti-Human Hvem (TNFRSF14) Antibodies And Uses Thereof
WO2023023489A3 (fr) * 2021-08-17 2023-03-30 Hemogenyx Pharmaceuticals Llc Anticorps bispécifiques anti-flt3/cd3 et leurs méthodes d'utilisation

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US11104738B2 (en) 2016-04-04 2021-08-31 Hemogenyx Pharmaceuticals Llc Monoclonal antibodies to human FLT3/FLK2 receptor protein
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AU2018220734B2 (en) * 2017-02-20 2025-03-06 Dragonfly Therapeutics, Inc. Proteins binding CD33, NKG2D and CD16
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US20190016802A1 (en) 2017-07-14 2019-01-17 Immatics Biotechnologies Gmbh Dual specificity polypeptide molecule
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CA3090244A1 (fr) 2018-02-08 2019-08-15 Dragonfly Therapeutics, Inc. Domaines variables d'anticorps ciblant le recepteur nkg2d
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US10654944B2 (en) * 2018-04-10 2020-05-19 Y-Biologics Inc. Cell engaging binding molecules
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WO2020167957A1 (fr) * 2019-02-12 2020-08-20 Board Of Regents, The University Of Texas System Récepteurs de cellules t ingéniérisés de haute affinité ciblant des cellules infectées par le cmv
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AU2020263910A1 (en) 2019-04-25 2021-10-21 F. Hoffmann-La Roche Ag Activatable therapeutic multispecific polypeptides with extended half-life
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AU2020279224B2 (en) 2019-05-21 2024-12-05 Novartis Ag Trispecific binding molecules against BCMA and uses thereof
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AU2021268340A1 (en) 2020-05-06 2022-12-08 Dragonfly Therapeutics, Inc. Proteins binding NKG2D, CD16 and CLEC12A
JP2023536665A (ja) * 2020-08-05 2023-08-28 オハイオ・ステイト・イノベーション・ファウンデーション アダプターポリペプチドおよびその使用方法
CN114478788B (zh) * 2020-11-11 2025-07-18 北京免疫方舟医药科技有限公司 一种同时靶向cd3和cd137的融合蛋白及其制备方法和用途
EP4301774A4 (fr) 2021-03-03 2025-08-13 Dragonfly Therapeutics Inc Méthodes de traitement du cancer à l'aide de protéines de liaison multi-spécifiques qui se lient à nkg2d, à cd16 et à un antigène associé à une tumeur
CA3217894A1 (fr) * 2021-05-28 2022-12-01 Gernot Stuhler Molecules de liaison proteiques recombinantes
AU2022318255A1 (en) 2021-07-27 2024-01-18 Morphosys Ag Combinations of antigen binding molecules
WO2024104988A1 (fr) 2022-11-15 2024-05-23 F. Hoffmann-La Roche Ag Protéines de liaison recombinantes ayant un domaine effecteur activable
WO2025217523A1 (fr) * 2024-04-12 2025-10-16 23Andme, Inc. Variant de charnière et molécules le comprenant
WO2025237931A1 (fr) 2024-05-15 2025-11-20 F. Hoffmann-La Roche Ag Protéines de liaison recombinantes avec lymphocytes t activables de manière conditionnelle et domaines effecteurs recrutant des cellules nk

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